Agent for prophylaxis or treatment of inflammatory bowel diseases

ABSTRACT

The present invention provides a novel agent for prophylaxis or treatment of inflammatory bowel diseases for oral administration or intra-intestinal infusion, which comprises as an active ingredient a compound of the formula (I):  
                 
 
     or a pharmaceutically acceptable salt thereof; a use of said active ingredient in preparation of an agent for prophylaxis or treatment of inflammatory bowel diseases; and a method for prophylaxis or treatment of inflammatory bowel diseases.

TECHNICAL FIELD

[0001] The present invention relates to a novel agent for prophylaxis ortreatment of inflammatory bowel diseases, more particularly an agent forprophylaxis or treatment of inflammatory bowel diseases which comprisesas an active ingredient sulfodehydroabietic acid or a pharmaceuticallyacceptable salt thereof, and a use of said active ingredient inpreparation of an agent for prophylaxis or treatment of inflammatorybowel diseases, and further relates to a method for prophylaxis ortreatment of inflammatory bowel diseases.

BACKGROUND ART

[0002] Inflammatory bowel diseases include intractable inflammatorydiseases of large and small intestines which are caused by variousnosogenesis, for example, ulcerative colitis which is a cryptogenicdiffuse non-specific inflammation wherein mucosa on the large intestineis mainly invaded and erosion and ulcer are formed, or Crohn's diseasewhich is a cryptogenic non-specific granulomatous inflammatory diseaseaccompanied by fibrosis or ulcer. In addition, the lesion of theintestine in Behçet's disease which is a chronic systemic inflammatorydisease is also included.

[0003] The nosogenesis of ulcerative colitis, Crohn's disease, orBehçet's disease has not been clarified yet, but their immunologicalmechanisms have recently attracted a lot of attentions. In themedication of these inflammatory bowel diseases, immunosupressants,steroids, salazosulfapyridine, etc. have been used, but they cannotexhibit sufficient effects in certain patients. Besides, they should beimproved with respect to side effects, and under these circumstances, ithas been desired to develop a medicament being more effective and havinga high safety.

[0004] On the other hand, sulfodehydroabietic acid or a salt thereof hasbeen known to exhibit an inhibitory activity of acid secretion or pepsinsecretion, etc., and to be useful as an agent for prophylaxis ortreatment of peptic ulcer (gastric ulcer, duodenal ulcer) or gastritis(JP-A-58-77814, JP-A-63-165361, JP-A-2-167258). It is considered thatpeptic ulcer (gastric ulcer, duodenal ulcer) or gastritis andinflammatory bowel diseases are different in not only their lesionregions, but also their nosogenesis is quite different. In thenosogenesis of peptic ulcer such as gastric ulcer and duodenal ulcer,the digestion by gastric juice cannot be left out of consideration. Inthe medication of these diseases, a medicament exhibiting an inhibitoryactivity of acid secretion such as a histamine H2 receptor antagonist ora proton pump inhibitor is mainly used in the medication of peptic ulcerand gastritis. On the other hand, an immunosupressant, a steroid, asalazosulfapyridine, etc. is mainly employed in the medication ofinflammatory bowel diseases, which is quite different from themedication of peptic ulcer or gastritis.

[0005] It has not been known at all that sulfodehydroabietic acid or asalt thereof is useful in the prophylaxis or treatment of inflammatorybowel diseases.

DISCLOSURE OF INVENTION

[0006] An object of the present invention is to provide a novel agentbeing useful in the prophylaxis or treatment of inflammatory boweldiseases.

[0007] During the studies on a novel remedy for inflammatory boweldiseases, the present inventors have found that sulfodehydroabietic aciddisclosed in JP-A-58-77814, JP-A-63-165361, etc. or a pharmaceuticallyacceptable salt thereof exhibits an excellent effect in the prophylaxisor treatment of inflammatory bowel diseases, and have accomplished thepresent invention.

[0008] That is, the present invention provides an agent for prophylaxisor treatment of inflammatory bowel diseases, which comprises as anactive ingredient sulfodehydroabietic acid (chemical name:(+)-(1R,4aS,10aR)-1,2,3,4,4a,9,10,10a-octadehydro-1,4a-dimethyl-7-(1-methylethyl)-6-sulfo-1-phenanthrenecarboxylicacid) of the following formula (1):

[0009] or a pharmaceutically acceptable salt thereof.

[0010] The present invention also relates to a use of saidsulfodehydroabietic acid (I) or a pharmaceutically acceptable saltthereof in preparation of an agent for prophylaxis or treatment ofinflammatory bowel diseases.

[0011] Moreover, the present invention provides a method for prophylaxisor treatment of inflammatory bowel diseases which comprisesadministering said sulfodehydroabietic acid (I) or a pharmaceuticallyacceptable salt thereof orally or parenterally to a patient beingsuffering from an inflammatory bowel disease.

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] The active ingredient of the present agent for prophylaxis ortreatment of inflammatory bowel diseases, sulfodehydroabietic acid ofthe formula (I) or a pharmaceutically acceptable salt thereof, is aknown compound, and can be prepared, for example, by the methodsdisclosed in JP-A-58-77814, JP-A-63-165361, JP-A-2-167258, or by amodified method thereof.

[0013] The pharmaceutically acceptable salt of sulfodehydroabietic acidof the formula (I) includes, for example, a salt with an alkali metal(e.g., sodium, lithium, potassium, etc.), a salt with an alkaline earthmetal (e.g., magnesium, calcium, etc.), and a salt with a metal such asaluminum. Among them, the preferable salt is a sodium salt ofsulfodehydroabietic acid, especially a monosodium salt or a disodiumsalt thereof, and the most preferable salt is sulfodehydroabietic acidmonosodium salt. Sulfodehydroabietic acid monosodium salt is moreadvantageous than disodium salt thereof as being less hygroscopic andbeing more stable (JP-A-63-165361). Besides, a pharmaceuticallyacceptable salt of sulfodehydroabietic acid may exist as well in theform of a hydrate thereof, and the hydrate of sulfodehydroabietic acidmonosodium salt may be, for example, pentahydrate thereof, i.e.,sulfodehydroabietic acid monosodium salt pentahydrate. The monosodiumsalt pentahydrate of sulfodehydroabietic acid of the formula (I)(chemical name:(+)-(1R,4aS,10aR)-1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-6-sulfo-1-phenanthrenecarboxylicacid 6-sodium salt pentahydrate) has been known as Ecabet sodium.

[0014] According to the study of the present inventors,sulfodehydro-abietic acid (I) or a pharmaceutically acceptable saltthereof of the active ingredient is hardly absorbed at the gut, and whenit is administered orally, it can efficiently reach to the inferior gutand can adhere to the mucosa of the lesion site, and exhibit thepharmacological effects thereof so that the efficacy thereof isextremely excellent. In addition, sulfodehydroabietic acid (I) or apharmaceutically acceptable salt thereof of the active ingredient showsfew side effects, and the safety thereof is extremely high.

[0015] The agent for prophylaxis or treatment of inflammatory boweldiseases of the present invention is effective on the lesion of theintestine (including fistula) in Crohn's disease, the lesion of theintestine in Behçet's diseases, ulcerative colitis, hemorrhagic rectalulcer, ileum pouchitis, etc.

[0016] Besides, since sulfodehydroabietic acid (I) or a pharmaceuticallyacceptable salt thereof of the active ingredient of the presentinvention can cure the lesion of the gut without causing a stenosis, itmay also be useful in the prophylaxis of the stenosis of the gut,especially in the prophylaxis of the stenosis of the intestineaccompanying with inflammatory bowel diseases. When surgically treatinga patient of an inflammatory bowel disease, an artificial anus may beconstructed, but in said patient, such an inflammation may occasionallyspread to the periphery of the artificial anus. The sulfodehydroabieticacid (I) or a pharmaceutically acceptable salt thereof of the activeingredient of the present invention is also effective in theinflammation of artificial anus periphery.

[0017] The sulfodehydroabietic acid (I) or a pharmaceutically acceptablesalt thereof of the active ingredient of the present invention may beadministered either orally or rectally, and further can be administereddirectly into the intestine through an artificial anus in a patienthaving one, or can directly be applied in the inflammation of theperiphery of ane artificial anus.

[0018] The present agent for prophylaxis or treatment of inflammatorybowel diseases can be used in the form of oral preparation,intra-intestinal infusion preparation, suppository preparation, orexternal preparation, which should be selected according to theadministration routes. Oral preparation may be solid preparations suchas tablets, capsules, powders, granules, or liquid preparation such assolutions, suspension, etc. A preparation being suitable for oraladministration may contain a pharmaceutically acceptable carrier orexcipient. A pharmaceutically acceptable carrier or excipient beingsuitable for a solid preparation such as tablets or capsules may be, forexample, binders (e.g., acacia, gelatin, dextrin,hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone), diluents(e.g., lactose, sucrose, mannitol, corn starch, potato starch, calciumphosphate, calcium citrate, crystalline cellulose), lubricants (e.g.,magnesium stearate, calcium stearate, stearic acid, talc, anhydroussilicic acid), disintegrants (e.g., corn starch, potato starch,carboxymethylcellulose, carboxymethylcellulose calcium, alginic acid),and wetting agents (e.g., sodium laurylsulfate). A pharmaceuticallyacceptable carrier or excipient being suitable for a liquid preparationsuch as solutions or suspensions may be, for example, aqueous vehicles(e.g., water), suspending agents (e.g., acacia, gelatin, methylcellulose, carboxymethylcellulose sodium, hydroxymethyl-cellulose,aluminum stearate gel), surfactants (e.g., lecithin, sorbitanmonooleate, glycerin monostearate), and non-aqueous vehicles (e.g.,glycerin, propylene glycol, vegetable oil). Moreover, liquidpreparations may contain preservatives (e.g., p-hydroxybenzoic acidmethyl ester, p-hydroxybenzoic acid propyl ester), flavors, and/orcoloring agents.

[0019] The intra-intestinal infusion (enema) preparation may be in theform of aqueous solution or suspension using the above-mentioned aqueousvehicles or suspending agents. If necessary, the intra-intestinalinfusion preparation may be in the form of sol or gel preparation usinga thickening agent such as polyacrylic acid, gelatin, etc.

[0020] The suppository may be ones which are prepared by mixing theactive ingredient of the formula (I) or a pharmaceutically acceptablesalt thereof with a commercially available oily base such as Witepsole,etc., or a water-soluble base such as macrogol, glycerogelatin, etc. bya conventional method, and may be in the form of capsule-typesuppository, tablet-type suppository, or ointment-type suppository.

[0021] The external preparation may include external powderpreparations, ointments, creams, etc.

[0022] In the present specification, the term “prophylaxis or treatment”comprises the improvement of symptoms, the prevention of exacerbation,the maintainance of remission, the prevention of recrudescence, theprevention of the stenosis of the gut, and more comprises the preventionof recrudescence after surgical operation and the prevention of thestenosis of the operated region.

[0023] The dose of the compound (I) or a pharmaceutically acceptablesalt thereof of the active ingredient of the present agent may varyaccording to the administration route, age, weight or conditions of apatient, or severity of the disease to be cured, but the daily dosethereof for an adult is usually in the range of about 10 mg to 300mg/kg, preferably in the range of about 20 mg to 300 mg/kg, especiallyin the range of 50 mg/kg to 200 mg/kg.

[0024] In the present specification, the inflammatory bowel diseasesmean not only inflammatory bowel disease in a strict sense such asCrohn's disease, ulcerative colitis, but also inflammatory bowel diseasein a broad sense including the lesion of the intenstine accompanyingwith Behçet's disease, hemorrhagic rectal ulcer, ileum pouchitis,intestinal tuberculosis, ischemic enteritis, drug-induced colitis,radiation enteritis, infective enteritis, etc.

EXAMPLES

[0025] The present agent and its efficacy will be illustrated in moredetail by the following Experiments and Preparations.

[0026] Experiment 1

[0027] Prophylactic or Therapeutic Effect on Acetic Acid-InducedIntestinal Injury:

[0028] Sulfodehydroabietic acid monosodium salt pentachloride(hereinafter referred to as Ecabet sodium) of the active ingredient ofthe present invention was previously administered to Fischer rats, andthe prophylactic or therapeutic effect thereof on intestinal mucosalinjury induced by intra-intestinal infusion of acetic acid was studied.

[0029] Namely, granules containing Ecabet sodium (0.5 g, trade name:Gastrome granule, containing 1.0 g of Ecabet sodium per 1.5 g,hereinafter simply referred to as Ecabet sodium-containing granules)were suspended in a physiological saline, and the mixture was injectedintra-rectally to Fischer rats. One hour thereafter, a 25% acetic acidsolution was intra-rectally injected to the rats. Two hours after theadministration of acetic acid, the intestine was excised from the rats,and the histopathological changes in the surface of the intestinal innerwall was observed visually and with a microscope, and the injury of theintestinal mucosa was evaluated both macroscopically and histologically.In the control group, the same procedures were repeated except for thata physiological saline was administered instead of a suspension ofEcabet sodium-containing granules in a physiological saline.

[0030] In the results, the intestinal mucosal injury induced by aceticacid was broadly observed in the physiological saline-treated rats whilethe intestinal mucosal injury was hardly observed in the rats treatedwith Ecabet sodium of the active ingredient of the present invention, bywhich it is proved that the active compound (I) of the present inventionwas useful as an agent for prophylaxis or treatment of inflammatorybowel diseases. In addition, the degree of the intestine mucosal injurybetween the physiological saline-treated group and the Ecabetsodium-treated group was scored and compared according to the criteriaas mentioned below, which was based on the method for Classification andEvaluation of Macpherson, B. R. et al., Digestion, 17, p. 135-150(1978). The data is indicated in Table 1. TABLE 1 Degree of MacroscopicDegree of Injury Histological Injury Physiological saline-treated 11.6 ±0.2  10 ± 0.3 group (Control) Ecabet sodium-treated  1.3 ± 0.2 2.3 ± 0.4group

[0031] (1) Scoring criteria of degree of macroscopic injury:

[0032] (i) Visibility of the blood vessel on the mucosa: (Score) (i)Visibility of the blood vessel on the mucosa: Good 0 Medium degree (thevisible area is more than 1 half of the whole area) Bad (the visiblearea is less than half of the 2 whole area) Nil 3 (ii) Erythema: Nil 0Linear 1 Patch 2 Diffuse 3 (iii) Bleeding: Nil 0 Petechial 1 Patch 2Multiple 3 (iv) Erosion/ulcer: Nil 0 Small (less than 1 mm × 1 mm) 1Medium (less than 5 mm × 5 mm) 2 Large (5 mm × 5 mm or more) or multiple3

[0033] (2) Scoring criteria of degree of histological injury:

[0034] (i) Area of Injury: (Score) (i) Area of Injury Nil 0 Webbed 1Restricted to the basal or terminus region 2 Diffuse 3 (ii) Edema: Nil 0Low-grade 1 Medium-grade 2 High-degree 3 (iii) Bleeding: Nil 0 Webbed 1Restricted to the basal or terminus region 2 Diffuse 3 (iv)Erosion/ulcer: Nil 0 Upper layer of mucosa 1 Lower layer of mucosa 2Ulcerated 3

[0035] Experiment 2

[0036] Effect on TNBS-Induced Enteritis:

[0037] Ecabet sodium of the active ingredient of the present inventionwas administered to Fischer rats to which TNBS was previouslyintra-intestinally injected to induce chronic enteritis, and furtheracetic acid was administered to the rats. Prophylactic or therapeuticeffect of Ecabet sodium on the mucosal injury of the intestine inducedby acetic acid was studied.

[0038] Namely, a solution of TNBS (2,4,6-trinitrobenzenesulfonic acid)in 50% ethanol was injected intra-intestinally to Fischer rats at a doseof 50 mg per 1 kg of the body weight to give the TNBS-induced enteritis.Three weeks thereafter, Ecabet sodium-containing granules (0.5 g) wassuspended in a physiological saline, and the mixture was administeredintra-rectally to the rats. Thirty minutes thereafter, a 25% acetic acidsolution was intra-rectally injected to the rats, and two hours afterthe acetic acid administration, the intestine was excised from the rats,and the intestinal mucosal injury thereof was scored and evaluated bothmacroscopically and histologically in the same manner as in Experiment 1according to the Macpherson's method for Classification and Evaluation.In the control group, the same procedures were repeated except for thata physiological saline was administered instead of a suspension ofEcabet sodium-containing granules in a physiological saline.

[0039] The results are shown in Table 2. TABLE 2 Degree of MacroscopicDegree of Injury Histological Injury Physiological saline-treated  10 ±0.4 11.3 ± 0.5  group (Control) Ecabet sodium-treated  3.9 ± 0.3*  4.6 ±0.4* group

[0040] As shown in Table 2, the intestinal mucosal injury observed inthe physiological saline-treated rats was effectively inhibited in theEcabet sodium-treated rats, by which it is proved that the activecompound (I) of the present invention is useful as an agent forprophylaxis or treatment of inflammatory bowel diseases.

[0041] Experiment 3

[0042] Clinical Effects in a Patient of Behçet's Disease:

[0043] 1) Prehistory Prior to the Administration of the Present Agent:

[0044] The patient was a female of 26 years old, whose illness had beendiagnosed as intestinal Behçet's disease accompanying with the multipleulcerative lesion at the small intestine, and who had been medicallytreated (i.e., administration of a steroid, etc.). Then, the patient wasoperated surgically twice to excise the intestine on account of massivemelena and regional peritonitis but the lesion of the remainingintestine was exacerbated, and further ileus, melena, and peritonitissymptoms caused by anastomotic recrudescence appeared. In order toexcise the injured intestine, the abdomen of the patient was incised,but the injured area was so large that the intestine could not beexcised, so that a loop ileal artificial anus was installed foradministration of Ecabet sodium.

[0045] 2) Effects of the Administration of the Present Agent:

[0046] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were orallyadministered twice a day. Further, said granules (1.5 g) were pulverizedin a mortar, suspended in water, and the resultant was directlyadministered into the intestine through the artificial anus twice a day.After the administration of Ecabet sodium, the pain and the melenadisappeared in a several days. Moreover, the ulcerative lesion wasremarkably improved in the endoscopic finding at 2 weeks after the startof the administration, by which it was confirmed that the lesion wasalmost cured. Even 7 months after the start of the administration, therecrudescence has not been observed.

[0047] Experiment 4

[0048] Clinical Effects in a Patient of Crohn's Disease:

[0049] 1) Prehistory Prior to the Administration of the Present Agent:

[0050] The patient was a female of 21 years old, whose illness wasdiagnosed from the pathological data as large and small intestineCrohn's disease. The exacerbation and the remission were mutuallyrepeated, and the patient was treated with a conventional medicine, butthe exacerbation of the anal lesion and the bleeding at the intestinecould not be controlled. Although a surgical excision of the lesion wasconsidered, the area of the lesion was so large that it could not beexcised, and therefore, a loop ileal artificial anus was installed foradministration of Ecabet sodium.

[0051] 2) Effects of the Administration of the Present Agent:

[0052] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were pulverized in amortar, suspended in water, and the resultant was directly administeredinto the intestine through the artificial anus once a day. After theadministration, the patient was doing well, and the exacerbation of thecondition was not observed even after one year lapsed from the start ofthe administration.

[0053] When the intestinal tissue of the lesion was observed by anendoscope, the injury of the intestinal mucosa which was observed priorto the administration disappeared one year after the start of theadministration.

[0054] Experiment 5

[0055] Clinical Effects in Ulcerative Colitis:

[0056] 1) Prehistory Prior to the Administration of the Present Agent:

[0057] The patient was a female of 49 years old, whose illness wasdiagnosed as left-sided colon ulcerative colitis. The patient wasmedicated with mesalazine and a steroid, and treated withleukocytapheresis, but the rectal lesion was remained, and the symptomswere not improved any further. The inflammation was scored as MattsGrade 3 (Quarterly Journal of Medicine, New Series, No. 120, October1961), and it was so frail that it bled when the endoscopic examinationwas carried out.

[0058] 2) Effects of the Administration of the Present Agent:

[0059] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were pulverized in amortar, suspended in a physiological saline (20 ml), and the resultantwas rectally administered through the anus twice a day. After theadministration, the inflammation was remitted to Matts Grade 2, and theinflammation area was decreased. That is, when the intestine tissue atthe lesion was observed by an endoscope, the inflammation thereof wasremarkably improved at 11 days after the start of the Ecabet sodiumadministration, by which the excellent effect of Ecabet sodium wasconfirmed. In addition, even 5 months after the start of theadministration, the recrudescence was not observed.

[0060] Experiment 6

[0061] Clinical Effects in Ulcerative Colitis:

[0062] 1) Prehistory Prior to the Administration of the Present Agent:

[0063] The patient was a male of 27 years old, whose illness wasdiagnosed as left-sided colon ulcerative colitis. The patient wasmedicated with mesalazine, predonine and a steroid, by which theinflammation was controlled to a degree of disseminated ulcer at therectum, but further improvement was not obtained.

[0064] 2) Effects of the Administration of the Present Agent:

[0065] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were pulverized in amortar, suspended in a physiological saline (20 ml), and the resultantwas rectally administered through the anus twice a day. After theadministration, the ulcer was improved into a red scar. Namely, when theintestinal tissue of the lesion was observed with an endoscope, theulcer was turned into a red scar at 18 days after the start of theEcabet sodium administration. The intractable ulcer can hardly be curedinto a red scar, and hence, the remarkable effects of Ecabet sodium areconfirmed.

[0066] Experiment 7

[0067] Clinical Effects in Ulcerative Colitis:

[0068] 1) Prehistory Prior to the Administration of the Present Agent:

[0069] The patient was a female of 58 years old, whose illness wasdiagnosed as left-sided colon ulcerative colitis. The patient wasmedicated with salazosulfapyridine and predonine, and treated withleukocytapheresis, but the inflammation condition at the rectum couldnot be controlled, and the bleeding and the melena lasted.

[0070] 2) Effects of the Administration of the Present Agent:

[0071] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were pulverized in amortar, suspended in a physiological saline (20 ml), and the resultantwas rectally administered through the anus twice a day. After theadministration, the inflammation condition was remarkably improved, andonly a slight erythema was remained. Namely, when the intestinal tissueof the lesion was observed by an endoscope, the inflammation almostdisappeared at 12 days after the start of the Ecabet sodiumadministration, and the remarkable improvement of the symptoms wasobtained by the administration of Ecabet sodium.

[0072] The observations of the lesion after and before the Ecabet sodiumadministration in the cases of ulcerative colitis of Experiments 5-7 areshown in Table 3. TABLE 3 Before the administration After theadministration of Ecabet sodium of Ecabet sodium Experiment 5Inflammation of Matts Inflammation of Matts (49 years old Grade 3 Grade2 female) Area of inflammation was reduced Experiment 6 Intractableulcer Improvement into a red (27 years old scar male) Experiment 7Inflammation of mild to Improvement into a slight (58 years old moderateerythema female)

[0073] Experiment 8

[0074] Clinical Effects in Acute Hemorrhagic Rectal Ulcer:

[0075] 1) Prehistory Prior to the Administration of the Present Agent:

[0076] The patient was a male of 74 years old, who was hospitalized fortreatment of HCV-associated hepatocirrhosis, hepatocellular carcinomaand esophageal varices. After the endoscopic ossification treatment forthe esophageal varices was done, an acute hemorrhagic rectal ulcerappeared at whole of the lower rectum. The patient was treated withtotal parenteral nutrition for 52 days, but the conditions were notimproved.

[0077] 2) Effects of the Administration of the Present Agent:

[0078] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were suspended inwater, and the resultant was injected through the anus twice a day forabout 1.5 month. The ulcer was cured without any cicatricial stenosis.

[0079] Experiment 9

[0080] Clinical Effects in Acute Hemorrhagic Rectal Ulcer:

[0081] 1) Prehistory Prior to the Administration of the Present Agent:

[0082] The patient was a female of 72 years old, who was hospitalizedfor treatment of the right thighbone break. During the treatmentthereof, an acute hemorrhagic rectal ulcer occurred at whole of thelower rectum. The patient was treated with total parenteral nutrition,but the conditions were not improved.

[0083] 2) Effects of the Administration of the Present Agent:

[0084] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were suspended inwater, and the resultant was injected through the anus twice a day forabout 2.5 months. The ulcer was cured without any cicatricial stenosis.

[0085] Experiment 10

[0086] Clinical Effects in Acute Hemorrhagic Rectal Ulcer:

[0087] 1) Prehistory Prior to the Administration of the Present Agent:

[0088] The patient was a female of 79 years old, who was hospitalizedfor treatment of pancreatic cancer. During the treatment, an acutehemorrhagic rectal ulcer appeared at whole of the lower rectum.

[0089] 2) Effects of the Administration of the Present Agent:

[0090] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were suspended inwater, and the resultant was injected through the anus twice a day forabout 1 month. The ulcer was cured without any cicatricial stenosis.

[0091] Experiment 11

[0092] Clinical Effects in Ileum Pouchitis:

[0093] 1) Prehistory Prior to the Administration of the Present Agent:

[0094] The patient was a male of 42 years old. During the postoperativetreatment, ileum pouchitis accompanying with acute hemorrhagic ulcerappeared at the ileum pouch which was subjected to ileal pouch/analanastomosis by the operation for ulcerative colitis.

[0095] 2) Effects of the Administration of the Present Agent:

[0096] Ecabet sodium was administered to the patient mentioned above.That is, Ecabet sodium-containing granules (1.5 g) were suspended inwater, and the resultant was injected through the anus twice a day forabout 4 months. The ileum pouchitis and the ulcer were cured without anycicatricial stenosis.

[0097] Preparation 1

[0098] Ecabet sodium (700 g), D-mannitol (252.7 g), sodium chloride (20g), aspartame (5 g) and magnesium stearate (20 g) were granulated by awet granulator, and thereto were added L-menthol (0.3 g) and hydroussilicon dioxide (2 g), and the mixture was mixed to give granules.

[0099] Preparation 2

[0100] To Ecabet sodium (700 g), D-mannitol (255 g), sodium chloride (20g), aspartame (5 g) and magnesium stearate (20 g) were added water, andthe mixture was granulated by a wet granulator to give granules.

[0101] Preparation 3

[0102] Ecabet sodium (700 g), D-mannitol (175 g), sodium chloride (105g) and magnesium stearate (20 g) were mixed to give powders.

[0103] Preparation 4

[0104] Ecabet sodium (700 g), D-mannitol (265.8 g), sodium chloride (7g), aspartame (5 g) and magnesium stearate (20 g) were granulated by awet granulator, and thereto were added L-menthol (0.3 g) and hydroussilicon dioxide (2 g), and the mixture was mixed, and compressed with atableting machine to give tablets.

[0105] Preparation 5

[0106] Ecabet sodium (700 g), D-mannitol (242.7 g), potassium chloride(30 g), aspartame (5 g) and magnesium stearate (20 g) were granulatedwith a wet granulator, and thereto were added L-menthol (0.3 g) andhydrous silicon dioxide (2 g). The mixture was mixed to give granules.

[0107] Preparation 6

[0108] The preparation obtained in Preparation 1 was further pulverizedin a mortar, and the resultant (3 g) was suspended in water (100 ml) togive an intra-intestinal infusion preparation.

[0109] Preparation 7

[0110] The preparation obtained in Preparation 2 was further pulverizedin a mortar, and the resultant (1.5 g) was suspended in a physiologicalsaline (20 ml) to give an intra-intestinal infusion preparation.

INDUSTRIAL APPLICABILITY

[0111] The sulfodehydroabietic acid or a pharmaceutically acceptablesalt thereof of the active ingredient of the present invention is usefulin the prophylaxis or treatment of inflammatory bowel diseases, whichare different in nosogenosis from peptic ulcer or gastritis. Inaddition, the sulfodehydroabietic acid or a pharmaceutically acceptablesalt thereof of the active ingredient of the present invention is hardlyabsorbed at the gut so that it shows few side effects even by oraladministration, and can efficiently adhere to the mucous membrane of thetargeted intestine region and depress the inflammation thereof, by whichthe intestinal lesion can be prevented or cured, so that the prophylaxisor treatment of inflammatory bowel diseases can be achieved with quiteefficacy. Further, the agent of the present invention is also effectiveon intractable inflammatory bowel diseases which cannot be cured by aconventional therapy for inflammatory bowel diseases, and hence, thepresent agent is quite useful as an agent for prophylaxis or treatmentof inflammatory bowel diseases.

1. A method for prophylaxis or treatment of inflammation of artificialanus periphery, which comprises administering an effective amount of thecompound of the formula (I) or a pharmaceutically acceptable saltthereof to a patient in need.
 2. The method for prophylaxis or treatmentaccording to claim 1, wherein the pharmaceutically acceptable salt ofthe compound of the formula (I) is sulfodehydroabietic acid monosodiumsalt.